Transcript Antifungals
Antifungal Agents Lindsay Mayer Daniels, PharmD August 15, 2008 Polyenes—Amphotericin B MOA: Binds to ergosterol within the fungal cell membrane resulting in depolarization of the membrane and the formation of pores. The pores permit leakage of intracellular contents. Exhibits concentration dependent killing. Polyenes—Amphotericin B Spectrum of Activity – Broad spectrum antifungal – Active against most molds and yeasts – Holes: C. lusitanae, Fusarium, Tricosporon, Scedosporium Histoplasma Fusarium Tricosporon Scedosporidium Zygomycetes ++ +++ + + + + -- Blastomyces lusitanae +++ +++ parapsilosis +++ Coccidioides tropicalis +++ +++ krusei ++ Cryptococcus glabrata +++ ++ albicans Aspergillus Candida Polyenes—Amphotericin B Resistance – Susceptibility testing methods have not been standardized – Development of resistance in a previously susceptible species is uncommon – Proposed mechanisms Reductions in ergosterol biosynthesis Synthesis of alternative sterols that lessen the ability of amphotericin B to interact with the fungal membrane Polyenes—Amphotericin B Isolated from Streptococcus nodosus in 1955 Amphotericin B is “amphoteric” – Soluble in both basic and acidic environments – Insoluble in water Formulations Amphotericin B deoxycholate – Fungizone Amphotericin B colloidal dispersion – Amphotec, Amphocil Amphotericin B lipid complex – Abelect Liposomal amphotericin B – Ambisome Amphotericin B deoxycholate Distributes quickly out of blood and into liver and other organs and slowly re-enters circulation – Long terminal-phase half-life (15 days) Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bone Disadvantages – Glomerular Nephrotoxicity—Dose-dependent decrease in GFR because of vasoconstrictive effect on afferent renal arterioles Permanent loss of renal function is related to the total cumulative dose – Tubular Nephrotoxicity—K, Mg+, and bicarbonate wasting – Decreased erythropoietin production – Acute Reactions—chills, fevers, tachypnea Support – – – – – Fluids K and Mag replacement Avoid concurrent nephrotoxic agents Premed with acetaminophen, diphenhydramine or hydrocortisone Meperidine for rigors Dose: 0.3 to 1 mg/kg once daily Amphotericin B Colloidal Dispersion (Amphotec) Cholesterol sulfate in equimolar amounts to amphotericin B Similar kinetics to amphotericin B deoxycholate Acute infusion related reactions similar to amphotericin B deoxycholate Reduced rates of nephrotoxicity compared to amphotericin B deoxycholate Dose – 3 to 4 mg/kg once daily Amphotericin B Lipid Complex (Abelcet) Equimolar concentrations of amphotericin and lipid Distributed into tissues more rapidly than amphotericin B deoxycholate – Lower Cmax and smaller AUC than amphotericin deoxycholate – Highest levels achieved in spleen, liver, and lungs – Delivers drug into the lung more rapidly than Ambisome – Lowest levels in lymph nodes, kidneys, heart, and brain Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity Dose – 5 mg/kg once daily Liposomal Amphotericin B (AmBisome) Liposomal product – One molecule of amphotericin B per 9 molecules of lipid Distribution – – – – Higher Cmax and larger AUC Higher concentrations achieved in liver, lung, and spleen Lower concentrations in kidneys, brain, lymph nodes and heart May achieve higher brain concentrations compared to other amphotericin B formulations Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity Dose – 3 to 6 mg/kg once daily Flucytosine Fluorinated pyrimidine MOA – Converted by cytosine deaminase into 5-fluorouracil which is then converted through a series of steps to 5fluorouridine triphosphate and incorporated into fungal RNA leading to miscoding – Also converted by a series of steps to 5-fluorodeoxyuridine monophosphate which is a noncompetitive inhibitor of thymidylate synthase, interfering with DNA synthesis Flucytosine Spectrum of Activity – Active against Candida species except C. krusei Cryptococcus neoformans Aspergillus species – Synergy with amphotericin B has been demonstrated The altered permeability of the fungal cell membrane produced by amphotericin allows enhanced uptake of flucytosine Mechanisms of Resistance – Loss of cytosine permease that permits flucytosine to cross the fungal cell membrane – Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesis Resistance occurs frequently and rapidly when flucytosine is given as monotherapy Always use combination therapy Flucytosine Half-life – 2 to 5 hours in normal renal function – 85 hours in patients with anuria Distributes into tissues, CSF, and body fluids Toxicities – Bone marrow suppression (dose dependent) – Hepatotoxicity (dose dependent) – Enterocolitis Toxicities occur more commonly in patients with renal impairment Dose – Administered orally (available in 250 and 500 mg capsules) – 100 to 150 mg/kg/day in 4 divided doses – Dose adjust for creatinine clearance Flucytosine concentrations should be monitored especially in patients with changing renal function Contraindicated in pregnancy Triazoles MOA: Inhibits 14-αsterol demethylase, which is a microsomal CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes Triazoles—Spectrum of Activity Fluconazole Itraconazole Voriconazole Posaconazole C. albicans +++ ++ +++ +++ C. glabrata + + ++ ++ C. krusei -- + +++ ++ C. tropicalis +++ ++ +++ +++ C. parapsilosis +++ ++ +++ +++ C. lusitanae ++ ++ +++ +++ Aspergillus -- ++ +++ +++ Cryptococcus +++ +++ +++ +++ Coccidioides +++ +++ +++ +++ Blastomyces ++ +++ ++ +++ Histoplasma + +++ ++ +++ Fusarium -- -- ++ ++ Scedosporium -- +/- + +/- Zygomycetes - - - ++ Triazoles—ADME Fluconazole Absorption IV and PO Good bioavailability Itraconazole PO Capsule ≠ Suspension Capsules best absorbed with food. Suspension best absorbed on empty stomach. Voriconazole Posaconazole IV and PO 90% oral bioavailability PO--Absorption enhanced with high fat meal Distribution Wide. Good CNS penetration Low urinary levels Poor CNS penetration Wide. Good CNS penetration Widely distributed into tissues Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19, 3A4 Saturable metabolism Not a substrate of or metabolized by P450, but it is an Inhibitor of 3A4 Minimal renal excretion Minimal renal excretion of parent compound 66% excreted in feces Elimination 80% excreted Excreted in feces unchanged in the urine Triazoles—Fluconazole Dose – 100 to 800 mg daily – Renal impairment: CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session Drug Interactions – Minor inhibitor of CYP 3A4 – Moderate inhibitor of CYP 2C9 Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas Adverse Drug Reactions – Well tolerated – Nausea – Elevated LFTs Dose Triazoles—Itraconazole – 200 to 400 mg/day (capsules) doses exceeding 200 mg/day are given in 2 divided doses Loading dose: 200 mg 3 times daily can be given for the first 3 days – Oral solution is 60% more bioavailable than the capsules Drug Interactions – Major substrate of CYP 3A4 – Strong inhibitor of CYP 3A4 – Many Drug Interactions Adverse Drug Reactions – Contraindicated in patients with CHF due to negative inotropic effects – QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactions – Hepatotoxicity – Rash – Hypokalemia – Nausea and vomiting Triazoles—Voriconazole Dose – IV 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours – PO > 40 kg—200-300 mg PO every 12 hours < 40 kg—100-150 mg PO every 12 hours Cirrhosis: – IV 6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours – PO > 40 kg—100 mg PO every 12 hours < 40 kg— 50 mg PO every 12 hours Renal impairment: if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer Triazoles—Voriconazole Drug Interactions Major substrate of CYP 2CD and 2C19 Minor substrate of CYP 3A4 Weak inhibitor of CYP 2C9 and 2C19 Moderate inhibitor of CYP 3A4 Common Adverse Effects – Peripheral edema – Rash (6%) – N/V/D – Hepatotoxicity – Headache – Visual disturbance (30%) – Fever Dose Adjustments Efavirenz Phenytoin Cyclosporine Warfarin Tacrolimus Serious Adverse Events – Stevens-Johnson Syndrome – Liver failure – Anaphylaxis – Renal failure – QTc prolongation Triazoles—Posaconazole Dosing (only available PO) – Prophylaxis of invasive Aspergillus and Candida species 200 mg 3 times/day – Treatment of oropharyngeal candidiasis 100 mg twice daily for 1 day, then 100 mg once daily for 13 days – Treatment or refractory oropharyngeal candidiasis 400 mg twice daily – Treatment of refractory invasive fungal infections (unlabeled use) 800 mg/day in divided doses Drug Interactions – Moderate inhibitor of CYP3A4 Adverse Reactions – Hepatotoxicity – QTc prolongation – GI: Diarrhea Echinocandins MOA Irreversibly inhibits B-1,3 –D glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall. Disruption of B1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture, and cell death. Echinocandins—Spectrum of Activity Histoplasma Fusarium Scedosporidium Zygomycetes -- - - - + ++ guilliermondii +++ Blastomyces lusitanae + ++ parapsilosis +++ Coccidioides tropicalis +++ -- krusei +++ Cryptococcus glabrata +++ +++ albicans Aspergillus Candida Echinocandins Caspofungin Micafungin Anidulafungin Absorption Not orally absorbed. IV only Distribution Extensive into the tissues, minimal CNS penetration Metabolism spontaneous degradation, hydrolysis and N-acetylation Elimination Chemical degradated Not hepatically metabolized Limited urinary excretion. Not dialyzable Half-life 9-23 hours 11-21 hours 26.5 hours Dose 70 mg IV on day 1, then 50 mg IV daily thereafter 100 mg IV once daily 200 mg IV on day 1, then 100 mg IV daily thereafter Dose Adjustment Child-Pugh 7-9 70 mg IV on day 1, then 35 mg IV daily thereafter CYP inducers 70 mg IV daily None None Echinocandin—Drug Interactions Caspofungin – Not an inducer or inhibitor of CYP enzymes – CYP inducers (i.e. phenytoin, rifampin, carbamazepine) Reduced caspofungin levels – Increase caspofungin dose – Cyclosporine Increases AUC of caspofungin Hepatotoxicity – Avoid or monitor LFTs – Tacrolimus Reduced tacrolimus levels by 20% – Monitor levels of tacrolimus Micafungin – Minor substrate and weak inhibitor of CYP3A4 – Nifedipine Increased AUC (18%) and Cmax (42%) of nifedipine – Sirolimus Increased concentration of sirolimus Anidulafungin – No clinically significant interactions Echinocandins—Adverse Effects Generally well tolerated Phlebitis, GI side effects, Hypokalemia Abnormal liver function tests Caspofungin – Tends to have higher frequency of liver related laboratory abnormalities – Higher frequency of infusion related pain and phlebitis References Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268 UNC Hospital Formulary Patel R. Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine. Mayo Clin Proc 1998;73:1205-1225 Terrel CL. Antifungal Agents. Part II. The Azoles. Mayo Clin Proc 1999;74:78100. Mehta J. Do variations in molecular structure affect the clinical efficacy and safety of lipid based amphotericin B preparations? Leuk Res. 1997;21:183-188. Groll AH et al. Penetration of lipid formulations of amphotericin B into cerebral fluid and brain tissue. 37th ICAAC, 1997. Abstract A90. Gallagher JC et al. Recent advances in antifungal pharmacotherapy for invasive fungal infections. Expert Rev. Anti-infect. Ther 2004; 2: 253-268. Groll AH et al. Antifungal Agents: In vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis 2004;23:256-270. Capelletty D et al. The echinocandins. Pharmacotherapy 2007;27:369-388. Spanakis EK et al. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006;43:1060-8. Rex JH, Stevens DA. Systemic Antifungal Agents. In: Mandell GL, Bennet JE, Dolin R, eds. Mandell, Douglas, and Bennett’s: Principles and Practice of Infectious Diseases. Vol 1. 6th ed. New York, NY: McGraw-Hill;2005:502.